Process of making acidyl morphin esters.



"UNITED STATES ERNST ll/I EN-NEL, OF DARMSTADT,

PROCESS OF MAKlNG ,ACIDYL MORPHIN ESTERS'.

SPEOIFIOATIOR forming part of Letters Patent No. 650,408, dated. May 29,1900.

:lppllcation filed August 9, 1899- Serle11i'o. 726,698. (No specimens-li v i i To allwhom itimaty concern.-

- Be it known that I, ERNST MENNEL, a subjeet of the Emperor of Germany,residing at Darmstadt, Germany, have invented a certain new and useful-Chemical Process, of which the following is a vfu'll, clear, and exactdescription. Carboxy-alkylic esters of morphin prepared according toOttos process'possess but little to stability and little tendency tocrystallize.

Their acidyl compounds, on the other hand,

exhibit decided crystallizability and comparaponnds can be obtained fromthe simple alx 5 pha-acidyl-morphins of the fatty-acid seriesas,-forinstance, aeetyl-mprphin, propionylmorphin, &c.'by treating the samewith .chlorocarboxylie esters and'alkali, preferably in molecularproportions,

' Carboxy-alkylic esters of morphin, as mentioned by Otto, arerepresented by this general typical formula:

OH ocoon' in which, Rsignifies anyfunivalent alcohol radical, (oralkyl'.)

' The carboxy-alkylic esters of acidyl-mor- 3o phins, which form thesubject of my'invention, are represented by this general typicalformula: j

" in which R'signifie's as before, and A signifies any'acid radical (oracidyl) of the fatty series. 4 p

Thereaction by which the carboxy-alkylic esters of acidyl-morphin's areformed in my process is represented by the-following equation:

0,,n,,no

wer

-0 in which R' and t signify as before rand 1n" GERMANY, AssIeNoR'ToLouls' unnoie' E. A'. MERCK, WILLY MERGE; AND 0. E. MERCK, or SAMEPLACE,

net in its other side chain.

signifies an alkali metal, (univalent in the instance here'shown or (theabove equation being translated into common language) An acidyl-morphinan alkali hy- :J it? vdrate-la chlorocarbo'xylic alkyl ester 5 5 acarboxv alkylic ester of an aci'dyLmor l phin an alkali ehlorid -water.Takingan actual specific example, in which? ,0,

A shall signify acetyl and R shall signifye' ethyl and M shall signifypotassium,th ef above e nation takes the followin 'forinz tivestability. Ihave'found that such comv q I otassinm. chlorocarboxylicACBAWI'mOXphII} hydroxid' ethyl ester I acetyl-rnorphin In a similardouble decomposition,"onlyiising: other chloroearboxylic esters insteadof" the ethyl ester, as above, we-obtain, for instanc carboxy-inethylicester of acetyl morphin o. .oo0oH, '1" so or carboxy-propylic ester ofacetyl-inorphin:

Q17Hfi v 0.0000,, 7 35 & c. Also by using other acidyl-morphins---v as,for instance, propionylmorphin or bu- CH H . tyr'y'l morphin-instead ofthe acetyl mor ph in we can vary the composition of the prod Otheralkalies go as, for instance, sodiuin hydroxid--can also be substitutedfor the potassium hydroxid as the agent for inducing the above-recitedreaction; but this will not yield a different 4 product, but is merely avariation possibly hearing on the convenience of manipulation or theeconomy of the process.-

As an example of my process, a, suitable acidyl-morphin, being suspendedin benzene,

is shakena'tordinary temperatures with the ce.

' successive small portions,

mg into solution with the benzene, while the alkali chlorid formed as aby-product is found dissolved in the aqueous liquor. The reaction beingcompleted, the benzene solution is siphoned off, washed, and dried. Onevaporating the-solvent herefrom the acidyl-mcrphin carboxy-alkylicester in a nearly-pure state is found as the residue.

Example of manufacture.-Aeetyl mow phin carboxyethylic esfer..0nethousand grams of alpha-acetyl-morphin, finely powdered, is suspended intwelve kilograms of benzene and three hundred and thirty grams ofchlorocarboxylic ethyl ester is added. Into this mixture one hundred andsixtyone grains of potassa in about ten-per-ceut. solution is allowed toflow in small portions,while the mixture is vigorously shaken. When thealkaline solution has all been added, the previously-prevailing odor ofthe chlorocarboxylic ethyl ester disappears. After the settling of theliquids the beuzenic stratum is siphoned off. This part having beenwashed with water and then dried, the benzene is distilled ofi. Thedesired ester in nearly a pure state remains as a solid crystallinemass. By recrystallizing it from three to four times its bulk ofabsolute alcohol it is obtained in beautiful glass-like needles orprisms, which melt at 150 centigrade. By treating the prod- .uct, finelypowdered,with its exact molecular equivalent of titrated hydrochloricacidthehy- I drochlorate of the product is obtained in small colorlessneedles, which melt at 185 centigrade under evolution of gas. Theseneedles, in combination with platinic chlorid, yield a platinum doublesalt, which crystallizes in orange-colored little needles and whosemelting-point is about 210 centigrade.

'Aetyl-morphin carboxy-methylic ester is It will be obvious that manychanges maybe made in thedisclosure herein without departing froin thespirit of my invention.

What I claim is-- v 1. The process of preparing a carhoxy-al kylic esterof an acidyl-inorphin, which consists in treating an alpha-mono-acidylcompound ofi morphin, whose acidyl constituent, is ofi the fatty-acidseries, with a chlorocarboxyl'ic ester and an alkali.

2. The process of preparing a carboxy-alkylic ester of anacidyl-morphin, which consists in treating an alpha-mono-acidyl compoundof morphin, whose acidyl constituent is of the fatty-acid series, with achlorocarboxylic ester and an alkali, the same being used inmolecular"proportions.

3'. The process of treating alpha-monoacetyl-morphin withchlorocarboxylic ethyl ester and an alkali, thereby producing thecarboxy-ethylic ester of acetyl-morphiu.

Signed at Darmstadt, Germany, this 20th dayof July, 1899.

ERNST MENNEL.

Witnesses JEAN GRUN-D, RICHARD GUENTIIER.

